rs11631944

Variant names:

• chr15-74179953-A-G
• rs11631944
• NM_022369.4:c.*127T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022369.4(STRA6):​c.*127T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,301,488 control chromosomes in the GnomAD database, including 26,500 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2320 hom., cov: 33)
  • Exomes 𝑓: 0.19 (24180 hom.)
• Consequence: STRA6 NM_022369.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.30
• Publications: 11 publications found

Genes affected

STRA6 (HGNC:30650): (signaling receptor and transporter of retinol STRA6) The protein encoded by this gene is a membrane protein involved in the metabolism of retinol. The encoded protein acts as a receptor for retinol/retinol binding protein complexes. This protein removes the retinol from the complex and transports it across the cell membrane. Defects in this gene are a cause of syndromic microphthalmia type 9 (MCOPS9). Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

STRA6 Gene-Disease associations (from GenCC):

• Matthew-Wood syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• microphthalmia, isolated, with coloboma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRA6	NM_022369.4	c.*127T>C		3_prime_UTR_variant	Exon 19 of 19	ENST00000395105.9	NP_071764.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRA6	ENST00000395105.9	c.*127T>C		3_prime_UTR_variant	Exon 19 of 19	1	NM_022369.4	ENSP00000378537.4

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23812 AN: 152106 Hom.: 2316 Cov.: 33

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0901

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0308

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.124

GnomAD4 exome AF: 0.192 AC: 220690 AN: 1149264 Hom.: 24180 Cov.: 16 AF XY: 0.187 AC XY: 107162 AN XY: 572182

African (AFR) AF: 0.0873 AC: 2407 AN: 27556

American (AMR) AF: 0.0654 AC: 2599 AN: 39732

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 3861 AN: 20584

East Asian (EAS) AF: 0.000266 AC: 10 AN: 37628

South Asian (SAS) AF: 0.0466 AC: 3256 AN: 69906

European-Finnish (FIN) AF: 0.284 AC: 11471 AN: 40364

Middle Eastern (MID) AF: 0.0551 AC: 188 AN: 3410

European-Non Finnish (NFE) AF: 0.219 AC: 188218 AN: 860578

Other (OTH) AF: 0.175 AC: 8680 AN: 49506

GnomAD4 genome AF: 0.157 AC: 23824 AN: 152224 Hom.: 2320 Cov.: 33 AF XY: 0.155 AC XY: 11544 AN XY: 74422

African (AFR) AF: 0.0909 AC: 3775 AN: 41538

American (AMR) AF: 0.0899 AC: 1375 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 655 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5178

South Asian (SAS) AF: 0.0302 AC: 146 AN: 4830

European-Finnish (FIN) AF: 0.275 AC: 2916 AN: 10600

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14551 AN: 67994

Other (OTH) AF: 0.123 AC: 260 AN: 2112

Alfa AF: 0.176 Hom.: 3010

Bravo AF: 0.139

Asia WGS AF: 0.0300 AC: 103 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Matthew-Wood syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.11
DANN	Benign	0.66
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11631944; hg19: chr15-74472294;